Feed-forward activator

A regulatory effect observed in many biochemical pathways an enzyme, which catalyzes a step (typically a late step) in a pathway, is activated by elevated levels of a precursor of a substrate for that enzyme. A possible example of feed-forward activation may be the action of elevated levels of fructose 1,6-bisphosphate on pyruvate kinase. 

CUMULATIVE FEEDBACK INHIBITION FEEDBACK INHIBITION FEED-FORWARD ACTIVATION "FELIX,"... 

Pyrimidine synthesis is controlled at the first committed step. ATP stimulates the aspartate transcarbamoylase reaction, while CTP inhibits it. CTP is a feedback inhibitor of the pathway, and ATP is a feed-forward activator. This regulation ensures that a balanced supply of purines and pyrimidines exists for RNA and synthesis. 

The flux through a metabolic pathway is invariably controlled or regulated, most commonly by Feedback Inhibition, but also through Feed-forward activation. Regulation is one of the things that makes biochemistry "biological" and it will be a focus in our study. 

Other small molecules can act as feed-forward activators. For example, in DNA synthesis, the amounts of purine and pyrimidine nucleotides must be kept roughly equal. The enzyme aspartate tran-scarbamoylase is feedback-inhibited by CTP, the product of its metabolic pathway, and feed-forward-activated by ATP. If there is an excess of pyrimidines, inhibition by CTP slows the reaction, while if there is an excess of purines, ATP activates the enzyme, ultimately increasing the amount of pyrimidines in the cell. 

Pyruvate kinase is also activated by fructose-1,6-bisphosphate. Why fructose-1,6-bisphosphate It is an example of feed-forward activation. This glycolytic intermediate is controlled by its own enzyme system. If glycolysis is activated, then the activity of pyruvate kinase must also be increased in order to allow overall carbon flow through the pathway. Feed-forward activation ensures that the enzymes act in concert to the overall goal of energy production. 

Compounds that act as allosteric activators of enzymes are often precursors of the pathway, so this is a mechanism for feed-forward activation, increasing the activity of a controlling enzyme in anticipation of increased availability of substrate. 

As discussed in section 5.6.1, citrate leaves the mitochondria to act as a source of acetyl CoA for fatty acid synthesis only when there is an adequate amount to maintain citric acid cycle activity. As citrate accumulates in the cytosol, it acts as a feed-forward activator of acetyl CoA carboxylase, increasing the formation of malonyl CoA. 

If alanine accumulates in muscle, it acts as an allosteric inhibitor of pyruvate kinase, so reducing the rate at which pyruvate is formed. This end-product inhibition of pyruvate kinase by alanine is over-ridden by high concentrations of fructose bisphosphate, which acts as a feed-forward activator of pyruvate kinase. ATP is an inhibitor of pyruvate kinase, and at high concentrations acts to inhibit the enzyme. More importantly, ATP acts as an allosteric inhibitor of phosphofructokinase (section 10.2.2.1). This means that, under conditions in which the supply of ATP (which can be regarded as the end-product of all energy-yielding metabolic pathways) is more than adequate to meet requirements, the metabolism of glucose is inhibited. 

P is a vector of inputs and T a vector of target (desired) values. The command newff creates the feed-forward network, defines the activation functions and the training method. The default is Fevenberg-Marquardt back-propagation training since it is fast, but it does require a lot of memory. The train command trains the network, and in this case, the network is trained for 50 epochs. The results before and after training are plotted. 

The neurons in both the hidden and output layers perform summing and nonlinear mapping functions. The functions carried out by each neuron are illustrated in Fig. 2. Each neuron occupies a particular position in a feed-forward network and accepts inputs only from the neurons in the preceding layer and sends its outputs to other neurons in the succeeding layer. The inputs from other nodes are first weighted and then summed. This summing of the weighted inputs is carried out by a processor within the neuron. The sum that is obtained is called the activation of the neuron. Each activated neu-... 

Figure 20 Feed-forward neural network training and testing results with back-propagation training for solvent activity predictions in polar binaries (with learning parameter rj = O.l).

The basic component of the neural network is the neuron, a simple mathematical processing unit that takes one or more inputs and produces an output. For each neuron, every input has an associated weight that defines its relative importance, and the neuron simply computes the weighted sum of all the outputs and calculates an output. This is then modified by means of a transformation function (sometimes called a transfer or activation function) before being forwarded to another neuron. This simple processing unit is known as a perceptron, a feed-forward system in which the transfer of data is in the forward direction, from inputs to outputs, only. 

Feed-forward control is more likely to be focused on a reaction occurring at or near the end of a pathway. Compounds produced early in the pathway act to enhance the activity of the control enzyme and so prevent a back log of accumulated intermediates just before the control point. An example of feed-forward control is the action of glucose-6-phosphate, fructose-1,6-bisphosphate (F-l,6bisP) and phosphoenol pyruvate (PEP), all of which activate the enzyme pyruvate kinase in glycolysis in the liver. 

Feed-forward regulation In liver, pyruvate kinase is activated by fructose 1,6-bisphosphate, the product of the phosphofructo-kinase reaction. This feed-forward (instead of the more usual feedback) regulation has the effect of linking the two kinase activities increased phosphofructokinase activity results in elevated levels of fructose 1,6-bisphosphate, which activates pyruvate kinase. 

A second pattern of allosteric control may be referred to as precursor activation or feed-forward control. 

The first involves various feedback and feed forward control mechanisms associated with metabolic pathways. Here a chemical present in the cell, usually an end product of a metabolic sequence, will influence the activity of an enzyme at the beginning of the pathway. This is usually achieved by the presence of an allosteric enzyme whose properties are significantly changed by effector molecules (Fig. 5.31). 

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